Clinical Efficacy Not Demonstrated With CD40–CD40L Blockade in RA

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Researchers conducted a phase 2a study finding that BI 655064 is safe with reductions in activated B-cells, autoantibody production and resorption markers, but not clinically effective in treating rheumatoid arthritis.

Blockade of the CD40-CD40L pathway using BI 655064 has not shown clinical efficacy among individuals with rheumatoid arthritis and an insufficient response to methotrexate, according to a study recently published in the Annals of the Rheumatic Diseases. However, this treatment did demonstrate safety and reduced activated B-cells, bone resorption and inflammatory markers, and autoantibody production.

This phase 2a, double-blind, 12-week study included 67 individuals with active rheumatoid arthritis and an insufficient response to methotrexate, all of whom were aged 18 to 70 years. Participants were randomly assigned to 12 weeks of BI 655064 120 mg (n=44) or placebo (n=23). A 20% improvement at the 12-week mark in American College of Rheumatology criteria (ACR20) constituted the primary end point. Safety assessments were performed on participants in the treatment arm. Nonresponder imputation was used to analyze binary end points, whereas last observation carried forward was used to analyze nonbinary end points.

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The primary end point was not achieved at week 12. Among those in the treatment group, 30 (68.2%) participants achieved ACR20, compared with 10 (45.5%) of those in the placebo group (P =.064). A posterior mean intergroup difference of 33.0% was shown via Bayesian analysis. However, the use of BI 655064 correlated with improved levels of bone resorption and inflammatory markers such as receptor activator of nuclear factor-κB ligand, interleukin-6, and matrix metalloproteinase-3, though these were not statistically significant. Lower autoantibody concentrations were also found among the treatment group. No serious treatment-related events occurred.  

Limitations to this study include a small sample size, the lack of examination into a dose effect, and an imbalance of participants with low or normal C-reactive protein.

The study researchers conclude that “[although] blockade of the CD40–CD40L pathway with BI 655064 in [patients with an insufficient response to methotrexate and] [rheumatoid arthritis] resulted in marked changes in clinical and biological parameters, including reductions in activated B-cells, autoantibody production and inflammatory and bone resorption markers, with a favourable safety profile, clinical efficacy was not demonstrated in this small phase IIa study.”

This study was funded by Boehringer Ingelheim, with which several authors report associations. See the reference for a full list of disclosures.


Visvanathan S, Daniluk S, Ptaszyński R, et al. Effects of BI 655064, an antagonistic anti-CD40 antibody, on clinical and biomarker parameters in patients with active rheumatoid arthritis: a randomised, double-blind, placebo-controlled, phase IIa study [published online March 22, 2019]. Ann Rheum Dis. doi: 10.1136/annrheumdis-2018-214729